WO1994014809A1 - Derives anneles d'uracile - Google Patents

Derives anneles d'uracile Download PDF

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Publication number
WO1994014809A1
WO1994014809A1 PCT/EP1993/003605 EP9303605W WO9414809A1 WO 1994014809 A1 WO1994014809 A1 WO 1994014809A1 EP 9303605 W EP9303605 W EP 9303605W WO 9414809 A1 WO9414809 A1 WO 9414809A1
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Prior art keywords
alkyl
halogen
arl
hydrogen
substituted
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PCT/EP1993/003605
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German (de)
English (en)
Inventor
Thomas Bär
Wolf-Rüdiger Ulrich
Peter Zimmermann
Hildegard Boss
Rainer Boer
Wolfgang Ise
Volker Gekeler
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Byk Gulden Lomberg Chemische Fabrik Gmbh
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Application filed by Byk Gulden Lomberg Chemische Fabrik Gmbh filed Critical Byk Gulden Lomberg Chemische Fabrik Gmbh
Priority to AU58133/94A priority Critical patent/AU5813394A/en
Publication of WO1994014809A1 publication Critical patent/WO1994014809A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the invention relates to uracil derivatives which are used in the pharmaceutical industry for the production of medicaments.
  • the invention relates to compounds of the formula I (see attached formula sheet), in which Rl is 1-7C-alkyl, R2 is 1-7C-alkyl,
  • R3 is phenyl substituted by R31, R32 and R33 or naphthyl, phenanthrenyl, pyridyl, thienyl, furyl, benzothienyl or benzofuryl substituted by R34, R35 and R36, where
  • R31 is hydrogen, hydroxy, halogen, nitro, cyano, carboxyl, trifluoroethyl, 1-4C-alkyl, halogen-1-4C-alkyl, 1-4C-alkoxy, completely or partially substituted by fluorine-1-4C-alkoxy, Arl -0-, Arl-CH 2 -0-, Arl-CO-, 1-4C-alkoxycarbonyl, 1-4C-alkylcarbonyl, halogen-1-4C-alkylcarbonyl, 1-4C-alkylcarbonyloxy, 1-4C-alkylcarbo - nyloxy-1-4C-alkyl, hydroxy-1-4C-alkyl, amino, mono- or di-1-4C- alkylamino, mono- or di- (hydroxy-1-4C-alkyl) amino, mono- or di - (Halogen-1-4C-alkyl) amino, 1-4C-alkylcarbonylamino, halogen-1-4C-al
  • A is 1-20C-alkylene or the grouping A1-X-A2, in which AI is 1-17C-alkylene, X is 0 (oxygen), S (sulfur), SO (sulfinyl) or SO 2 (sulfonyl) and A2 2-18C-alkylene, where the sum of the alkylene carbon atoms of Al and A2 is not greater than 19, R5 Arl and
  • R6 means methyl [-CH (Arl) Ar2] or hydroxymethyl [-C (0H) (Arl) Ar2] substituted by Arl and Ar2, where
  • Arl phenyl or phenyl and Ar2 phenyl which are substituted by one or two identical or different substituents from the group hydroxyl, halogen, nitro, trifluoromethyl, 1-4C-alkyl and 1-4C-alkoxy or by one or two identical or different sub- is substituted by phenyl from the group of hydroxy, halogen, 1-4C-alkyl and 1-4C-alkoxy, and their salts.
  • 1-7C-Alkyl stands for straight-chain or branched alkyl radicals with 1 to 7 carbon atoms. Examples include heptyl, isoheptyl (2-methylhexyl), hexyl, isohexyl (2-methylpentyl), neohexyl (2,2-diethylbutyl), pentyl, isopentyl (3-methylbutyl) -), neopentyl- (2,2-di- methylpropyl), butyl, iso-butyl, sec.-butyl, tert.-butyl, propyl, isopropyl, ethyl and the methyl radical.
  • Halogen in the sense of the present invention is bromine, chlorine and fluorine.
  • 1-4C-Alkyl stands for straight-chain or branched alkyl radicals with 1 to 4 carbon atoms. Examples include the butyl, iso-butyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and methyl radicals.
  • Halogen-1-4C-alkyl stands for one of the 1-4C-alkyl radicals mentioned above which is substituted by one or more halogen atoms.
  • the chloromethyl radical or the 4-chlorobutyl radical may be mentioned as an example.
  • 1-4C-Alkoxy represents a radical which, in addition to the oxygen atom, contains one of the 1-4C-alkyl radicals mentioned above.
  • the methoxy and ethoxy radicals may be mentioned, for example.
  • 1,2,2-trifluoroethoxy, 2,2,3,3,3-pentafluoropropoxy, perfluoroethoxy and in particular 1,1,2 are examples of 1,2-trifluoroethoxy which are wholly or partly substituted by fluorine , 2-Tetraffuorethoxy-, the trifluoromethoxy, the 2,2,2-trifluoroethoxy and the difluoromethoxy called.
  • Arl-0- means phenoxy or phenoxy which is substituted by one or two identical or different substituents from the group consisting of hydroxyl, halogen, nitro, triffuormethyl, 1-4C-alkyl and 1-4C-alkoxy.
  • Arl-CH -0- means benzyloxy or benzyloxy which is substituted in the phenyl ring by one or two identical or different substituents from the group hydroxyl, halogen, nitro, triffuormethyl, 1-4C-alkyl and 1-4C-alkoxy.
  • Arl-CO- means benzoyl or benzoyl which is substituted by one or two identical or different substituents from the group consisting of hydroxyl, halogen, nitro, trifluoromethyl, 1-4C-al yl and 1-4C-alkoxy.
  • 1-4C-Alkoxycarbonyl stands for a carbonyl group to which one of the above-mentioned 1-4C-alkoxy radicals is attached.
  • the methoxycarbonyl (CH i O-CO-) and the ethoxycarbonyl (CH 3 CH 2 0-C0-) are mentioned.
  • 1-4C-A1kylcarbonyl represents a carbonyl group to which one of the 1-4C-A1kyl radicals mentioned above is bound.
  • the acetyl radical (CH 3 C0-) may be mentioned.
  • Halogen-1-4C-alkylcarbonyl stands for one of the above-mentioned 1-4C-alkylcarbonyl radicals which is substituted by one or more halogen atoms.
  • 1-4C-A1kylcarbonyloxy radicals contain one of the aforementioned 1-4C-A1kylcarbonyl radicals in addition to the oxygen atom.
  • the acetoxy residue (CH 3 C0-0-) may be mentioned.
  • 1-4C-A1kylcarbonyloxy-1-4C-alkyl represents one of the above-mentioned 1-4C-A1kylcarbonyloxy radicals which is bonded to one of the above-mentioned 1-4C-A1-alkyl radicals.
  • the acetoxymethyl radical may be mentioned.
  • Hydroxy-1-4C-alkyl represents one of the 1-4C-alkyl radicals mentioned above which is substituted by one or more hydroxyl radicals.
  • the hydroxymethyl radical or the 2-hydroxyethyl radical may be mentioned.
  • Examples of mono- or di-1-4C-alkylamino residues are methylamino, dimethylamino and diethylamino.
  • Mono- or di- (hydroxy-1-4C-alkyl) amino stands for an amino radical to which one or two of the above-mentioned hydroxy-1-4C-alkyl radicals are bound. Examples include the 2-hydroxyethylamino residue and the di- (2-hydroxyethyl) amino residue.
  • Mono- or di- (halogen-1-4C-alkyl) amino stands for an amino radical to which one or two of the above-mentioned Haiogen-1-4C-alkyl radicals are bound. For example, the triffuormethylamino residue and the di (2-chloroethyl) amino residue.
  • the 1-4C-A1kylcarbonylamino radical may be mentioned, for example, the acetylamido radical (-NH-CO-CH 3 ).
  • Halogen-1-4C-alkylcarbonylamino stands for an amino radical to which one of the above-mentioned halogen-1-4C-alkylcarbonyl radicals is bound.
  • the 5-chloropentanoylamino residue or the trifluoroacetylamino residue may be mentioned.
  • 1-4C-Alkylsulfonamido stands for a sulfonamido radical to which one of the 1-4C-alkyl radicals mentioned above is bound.
  • the methylsulfonamido radical may be mentioned.
  • the p-toluenesulfonamido radical may be mentioned as an example of a phenylsulfonamido radical substituted by R34, R35 and R36.
  • 1-4C-Alkylaminosulfonamido stands for a sulfamoyl radical to which one of the 1-4C-alkyl radicals mentioned above is bound.
  • the methyl sulfamido radical may be mentioned.
  • Exemplary phenyl radicals substituted by R31, R32 and R33 are the radicals phenyl, 4-acetamidophenyl, 3-acetamidophenyl, 4-acetoxyphenyl, 2-aminophenyl, 3-aminophenyl, 2-bromophenyl, 4-bromophenyl, 4-carboxyphenyl, 2- Chlorophenyl, 3-chlorophenyl.
  • Exemplary naphthyl, phenanttrenyl, pyridyl, thienyl, furyl, benzothienyl and benzofuryl radicals substituted by R34, R35 and R36 are the radicals 1-naphthyl, 2-naphthyl, 4-dimethylamino-1-naphthyl, 2-hydroxy-1-naphthyl, 4-hydroxy-1-naphthyl, 2-ethoxy-1-naphthyl, 4-methoxy-1-naphthyl, 9-phenanthrenyl, 1, 3-dichloro-6-trifluoromethyl-9- phenanthrenyl, 2-pyridyl, 3-pyridyl, 6-methyl-2-pyridyl, 2-thienyl, 3-thienyl, 4-bromo-2-thienyl, 5-bromo-2-thienyl, 5-nitro-2-thienyl, 5-chloro-2-thieny
  • 1-20C-alkylene stands for straight-chain or branched alkylene radicals with 1 to 20 carbon atoms. Examples are ethylene (-CH 2 CH 2 -), trimethylene (-CH 2 CH 2 CH 2 -), tetramethylene (-CH 2 CH 2 CH 2 CH 2 -), pentamethylene (-CH 2 CH 2 CH 2 CH 2 CH 2 -), hexamethylene (-CH 2 - (CH 2 ) 4 -CH 2 -), octamethylene (-CH 2 - (CH 2 ) 6 -CH 2 -), decamethylene (-CH 2 - (CH 2 ) 8 -CH 2 -), dodecamethylene (-CH 2 - (CH 2 ) 10 -CH 2 -), hexadecamethylene (-CH 2 - (CH 2 ) 14 -CH 2 -), octadecamethylene (-CH 2 - (CH 2 ) 16 -CH 2 ), 1,2-dimethylethylene [-CH (CH 3 )
  • Suitable salts for compounds of the formula I are preferably all acid addition salts. Particular mention should be made of the pharmacologically tolerable salts of the inorganic and organic acids usually used in galenics. Pharmacologically incompatible salts, which may initially be obtained as process products in the preparation of the compounds according to the invention on an industrial scale, are converted into pharmacologically acceptable salts by processes known to the person skilled in the art.
  • Suitable as such are water-soluble and water-insoluble acid addition salts with acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2- (4-hydroxybenzoyl) benzoic acid, butyric acid, sulfosalicylic acid, Maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 3-hydroxy-2-naphthoic acid, the acids used in salt production - depending on whether it is a mono- or polyacid acts and, depending on which salt is desired - be used in an equimolar or in a different proportion.
  • acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid
  • R3 is phenyl substituted by R31, R32 and R33 or naphthyl, phenanthrenyl, pyridyl, thienyl, furyl, benzothienyl or benzofuryl substituted by R34, R35 and R36, where R31 is hydrogen, hydroxy, halogen, nitro, cyano, triffuormethyl,
  • R34 is hydrogen, hydroxy, halogen, nitro, cyano, carboxyl, trifluoromethyl, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, 1-4C-alkylcarbonyloxy-1-4C-alkyl, hydroxy -l-4C-alkyl, amino, mono- or di-1-4C-alkylamino, 1-4C-A1kylcarbonylamino, Haiogen-1-4C-alkylcarbonylamino, l-4C-alkylsulfonamido or Arl, R35 hydrogen, hydroxy, halogen , 1-4C-A1kyl or 1-4C-alkoxy and R36 denotes hydrogen, halogen, 1-4C-A1kyl or 1-4C-alkoxy, R4 means 1-4C-alkyl,
  • A is 1-20C-alkylene or the grouping A1-X-A2, in which AI is 1-17C-alkylene, X is 0 (oxygen), S (sulfur), SO (sulfinyl) or SO 2 (sulfonyl) and A2 2-18C-alkylene, where the sum of the alkylene carbon atoms of Al and A2 is not greater than 19, R5 Arl and
  • R6 means methyl [-CH (Arl) Ar2] or hydroxymethyl [-C (0H) (Arl) Ar2] substituted by Arl and Ar2, where
  • Arl phenyl or phenyl and Ar2 phenyl substituted by one or two identical or different substituents from the group hydroxyl, halogen, nitro, triffuormethyl, 1-4C-alkyl and 1-4C-alkoxy or by one or two identical or different sub ⁇ is substituted by phenyl from the group of hydroxy, halogen, 1-4C-alkyl and 1-4C-alkoxy, and their salts.
  • Rl is 1-4C-alkyl
  • R2 is 1-4C-alkyl
  • R3 is phenyl substituted by R31, R32 and R33 or naphthyl
  • thienyl furyl
  • R31 hydrogen, halogen, nitro, cyano, trifformethyl, 1-4C-alkyl, 1-4C-alkoxy, phenyoxy, benzyloxy, benzoyl, amino, mono- or di-1-4C-alkylamino, mono- or di- (hydroxy- 1-4C-alkyl) amino, 1-4C-A1-alkylcarbonylamino, halogen-1-4C-alkylcarbonylamino, 1-4C-alkylsulfonamido, phenylsulfonamido substituted by R34, 1-4C-alkylaminosulfonamido, morpholino, pyrrolidino or piperidino
  • R32 is hydrogen, halogen or nitro
  • R33 is hydrogen, and where R34 is hydrogen, halogen, nitro, cyano, 1-4C-alkyl, 1-4C-alkoxy,
  • R35 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy and R36 is hydrogen or halogen
  • R4 is 1-4C-alkyl
  • A is 3-12C-alkylene means R5 Arl and
  • R6 means methyl [-CH (Arl) Ar2] or hydroxyethyl [-C (0H) (Arl) Ar2] substituted by Arl and Ar2, where
  • Arl is phenyl or phenyl substituted by one or two identical or different substituents from the group hydroxyl and halogen and Ar2 is phenyl or phenyl or substituted by one or two identical or different substituents from the group hydroxyl and halogen, and their salts.
  • Preferred compounds are those of the formula I in which Rl is 1-4C-alkyl, R2 is 1-4C-alkyl,
  • R3 is phenyl substituted by R31, R32 and R33 or naphthyl or thienyl substituted by R34, R35 and R36, where R31 is hydrogen, halogen, nitro, cyano, triffuormethyl, 1-4C-alkyl, 1-4C-alkoxy, phenoxy, amino, Mono- or di-1-4C-alkylamino, mono- or di- (hydroxy-1-4C-alkyl) amino, 1-4C-alkylcarbonylamino, 1-4C-alkylsulfonamido, phenylsulfone ido substituted by R34, 1-4C-alkylaminosulfonamido or morpholino, R32 is hydrogen, halogen or nitro and R33 is hydrogen, and where R34 is hydrogen, halogen, 1-4C-alkyl, amino or mono- or
  • R35 is hydrogen and R36 is hydrogen
  • R4 is 1-4C-alkyl
  • A is 3-10C-alkylene
  • R5 is Arl
  • R6 means hydroxymethyl [-C (0H) (Arl) Ar2] substituted by Arl and Ar2, where
  • Arl means phenyl or phenyl substituted by hydroxyl or halogen and Ar2 phenyl or phenyl or substituted by hydroxyl or halogen, and their salts.
  • the invention further relates to a process for the preparation of the compounds of the formula I and their salts.
  • the method is characterized in that
  • oxidation dehydrogenation
  • inorganic and organic oxidation agents such as, for example, manganese dioxide, nitric acid, chromium (VI) oxide, sulfur, cerium (IV) ammonium nitrate, alkali dichromate, nitrogen oxides, chloranil, tetracyanobenzoquinone or anodic oxidation in the presence of a suitable electrolyte system.
  • the compounds III and IV are reacted in a manner known for the preparation of tertiary amines.
  • the reaction can, if desired, be carried out in the presence of a base (for example an inorganic carbonate, such as potassium carbonate) and / or using an excess of amine IV become.
  • a base for example an inorganic carbonate, such as potassium carbonate
  • the reaction can be promoted by adding alkali iodide.
  • the reaction of the compounds III and IV is otherwise carried out in a manner which is known per se to the person skilled in the art and as described, for example, in European patent applications EP-A-242829 or EP-A-314038.
  • the compounds of the formula II are obtained in a manner known per se by reacting the compounds of the formula V (see attached formula sheet) with amines of the formula IV. This reaction takes place, for example, as described above in general or as described in the examples.
  • the compounds of the formula III are likewise obtained in a manner known per se by oxidation of the compounds of the formula V.
  • the oxidation is likewise carried out, for example, as described above in general or as described in the examples.
  • the compounds of the formula V are obtained in a manner known per se by reacting the compounds of the formula VI (see attached formula sheet) with compounds of the formula VII (see attached formula sheet).
  • the U set The compounds VI and VII are formed in a manner known per se to the person skilled in the art, for example as described in the examples.
  • the compounds of the formulas IV, VI and VII are known or they can be prepared in a manner known per se from corresponding starting compounds in an analogous manner.
  • the compounds VII are obtained, for example, by reacting diketones R4-CO-CH 2 -CO-AX with corresponding aldehydes R3-CH0.
  • Example 1 6- (5-chloropentanoyl) -2,4-dioxo-5- (3-triffuormethyl-phenyl) -1,3,7-trimethyl-pyrido [2,3-d] pyrimidine are reacted analogously to Example 1.
  • the crystalline line product has a melting point of 96-100 ⁇ C.
  • the title compound of mp 130-136 ⁇ C is obtained by reacting 6- (8-bromooctanoyl) -2,4-dioxo-5- (3-nitrophenyl) -1,3,7-trimethyl-pyrido [2,3- d] pyrimidine obtained analogously to Example 1 and hydrochloride formation. To do this, the base is dissolved in isopropyl acetate and precipitated as a salt by adding ethereal HC1.
  • the title compound is obtained analogously to Example 20 when the starting substance is 6- (11-bromundecanoyl) -5- (2-chloro-5-nitro-phenyl) -2,4-dioxo-1,3,7-tri-methyl -pyrido [2,3-d] pyrimidine is used.
  • the purification is carried out chromatographically on silica gel [petroleum ether / ethyl acetate / triethylamine (60: 40: 1)].
  • the product is dissolved in 100 ml of cyclohexane and precipitated with ethereal HC1 as the hydrochloride.
  • the salt melts at 100-124 ⁇ C.
  • the title compound is obtained analogously to Example 20 if 6- (II-bromundecanoyl) -5- (2-chloro-5-nitro-phenyl) -1, 3-dibutyl-2,4-di-oxo-7 is used as the starting substance -methyl-pyrido [2,3-d] pyrimidine is used.
  • the crude product is purified chromatographically on silica gel [petroleum ether / ethyl acetate / triethylamine (95: 5: 2)].
  • the fu arate melts at 146 ⁇ C (from ethanol).
  • the title compound is obtained analogously to Example 20 when the starting substance is 5- (2-bromo-5-thienyl) -6- (11-bromundecanoyl) -2,4-dioxo-1,3,7-trimethyl-pyrido [2 , 3-d] pyrimidine is used.
  • the crude product is purified chromatographically on silica gel [petroleum ether / ethyl acetate (60:40)].
  • the hydrochloride precipitated from ether with ethereal HC1 melts at 196 ⁇ C.
  • the title compound is obtained analogously to Example 20 if 6- (II-bromundecanoyl) -2,4-dioxo-5- (2-thienyl) -1,3,7-trimethyl-pyrido [2,3 -d] pyrimidine is used.
  • the crude product is purified chromatographically on silica gel [petroleum ether / ethyl acetate / triethylamine (90: 10: 3)].
  • the crystallized from aqueous HC1 base melts at 65-68 p C.
  • the resinous residue is boiled up with 20 ml of 0.1 N HC1 and triturated. The mixture is filtered, the residue is dried and the product is precipitated from acetone / ether. 401 mg (56%) of the title compound are obtained.
  • the hydrochloride sinters from 177 ⁇ C.
  • Example 296- (II-bromunde-canoyl) -5- (4-chloro-3-nitro-phenyl) -2,4-dioxo-1,3,7-trimethyl-pyrido [2, 3-d] - pyrimidine is used as the starting compound.
  • the hydrochloride sinters from 145 ⁇ C.
  • Example 26 The title compound is obtained when 5- (3-anilinyl) -2,4-dioxo-6- [5- (4-diphenylpiperidin-l-yl) pentanoyl] -1,3,7-trimethyl-pyrido [2, 3-d] pyrimidine (Example 26) is reacted analogously to Example 34 with tosyl chloride. The product is boiled with 0.5 N HC1, triturated and stirred in ether. The hydrochloride melts at 119 ⁇ C (foaming).
  • Example 26 The title compound is obtained when 5- (3-anilinyl) -2,4-dioxo-6- [5- (4-diphenylpiperidin-l-yl) pentanoyl] -1,3,7-trimethyl-pyrido [2, 3-d] pyrimidine (Example 26) is reacted analogously to Example 34 with 5-chloropentanoyl chloride.
  • the base absorbs 0.75 equivalents of HCl when boiled with 0.2 N HCl.
  • Mp of the hydrochloride 113 ⁇ C (sintering); 205 ⁇ C (foaming).
  • Example 26 5- (3-anilinyl) -2,4-dioxo-6- [5- (4-diphenylpiperidin-1-yl) pentanoyl] -1,3,7-trimethyl-pyrido [2,3-d] pyrimidine ( Example 26) is reacted with trifluoroacetyl chloride as in Example 34. Colorless foam.
  • Example B 1-chloro-6- (3-chlorobenzylidene) octane-5,7-dione is reacted.
  • the product melts at 118-120'C.
  • Example B 1-chloro-6- (3-phenoxy-benzylidene) octane-5,7-dione is reacted.
  • the title compound melts at 126 ⁇ C.
  • Example B Analogously to Example B, l-bromo-12- (2-chloro-5-nitro-benzylidene) tetradecane-11,13-dione is reacted with 6-amino-1,3-dibutyluracil. Amorphous foam.
  • AD 6- (5-Chloropentanoy1) -5- (4-N-diethanolamino-3-nitro-phenyl) -2,4-dioxole, 3,7-trimethyl-pyridor2,3-dlpyrimidine
  • the compounds of the formula I and their salts have valuable properties which make them commercially usable. They improve the effect of antibiotics and / or cytostatics in a synergistic manner and, moreover, they are able to overcome existing resistances to antibiotics and / or cytostatics that arise during the course of therapy. They can not only be used in combination with other cytostatics or antibiotics to overcome the so-called "drug resistance” or "multidrug resistance”. Rather, because of their antineoplastic properties, they are suitable per se for the treatment of tumor diseases, for example for reducing or preventing the formation of metastases and tumor growth in mammals, and because of their antiproliferative properties, for example for the treatment of dermatoses.
  • the excellent effectiveness of compounds of the formula I and their salts permits their use in human medicine as sole or accompanying chemotherapeutic agents for the treatment of tumors, for example leukemia, ovarian cancer, testicular tumors, prostate cancer, bladder tumors, kidney tumors, esophageal cancer and others malignant new tissue fertilizers, in particular colon cancer, breast cancer, bronchial carcinoma and lung cancer.
  • tumors for example leukemia, ovarian cancer, testicular tumors, prostate cancer, bladder tumors, kidney tumors, esophageal cancer and others malignant new tissue fertilizers, in particular colon cancer, breast cancer, bronchial carcinoma and lung cancer.
  • the compounds according to the invention can overcome the "drug resistance" of tumor cells, the resistance to certain malaria agents, such as chloroquine, can also be eliminated by the compounds according to the invention.
  • the compounds according to the invention are furthermore not only suitable for overcoming resistance to antibiotics. Rather, due to their antiparasitic properties, they can be used to treat parasitic, in particular tropical, parasitic diseases such as malaria, sleeping sickness, filariasis or onchocerciasis.
  • the dose of the cytostatics administered can be reduced, which leads to a significant reduction in the toxic side effects, and that the number of cytostatics that can be used increases , so that the cytostatic optimally suitable for the specific tumor and the specific patient can be specifically selected.
  • the compounds of the formula I and / or their pharmacologically tolerable salts are administered as resistance modulators in antibiotic and cytostatic therapy
  • the compounds of the formula I can be administered together with the antibiotics or cytostatic agents in a fixed dose in the form of combination preparations , or the compounds of formula I can be used separately in any dosage and in a suitable dosage form as accompanying and supporting active substances in antibiotic or cytostatic therapy.
  • the ratio of compound I to antibiotic or cytostatic depends on the disease to be treated, the patient's condition and the antibiotic or cytostatic used. It has generally proven to be advantageous here if the compounds of the formula I are administered orally in a daily dose of about 0.5 to 30 mg / kg of body weight, with an to be administered in a daily dose of approximately 0.1 to 10 mg / kg of body weight, if desired in the form of several single doses or as a continuous infusion to achieve the desired result.
  • the antibiotics or cytostatics are in the usual, but preferably ii; administered lower doses.
  • the invention also relates to the compounds of the formula I and their pharmacologically tolerable salts for use in the treatment of tumor diseases.
  • the invention also encompasses the use of compounds of the formula I and their pharmacologically tolerable salts in the manufacture of medicaments which are used to combat tumor diseases.
  • Another object of the invention is the use of compounds of formula I in combination with antibiotics or cytostatics in antibiotic and / or cytostatic therapy.
  • the invention also relates to the use of compounds of the formula I for the production of medicaments which are to be used in combination with antibiotics or cytostatics in antibiotic and / or cytostatic therapy.
  • the invention further relates to medicaments which contain one or more compounds of the general formula I and / or their pharmacologically tolerable salts.
  • the pharmaceuticals are produced by methods known per se and familiar to the person skilled in the art.
  • the person skilled in the art is familiar with the auxiliaries which are suitable for the desired pharmaceutical formulations on the basis of his specialist knowledge.
  • gel formers In addition to solvents, gel formers, suppository bases, tablet auxiliaries and other active substance carriers, for example antioxidants, dispersants, emulsifiers, defoamers, taste correctors, preservatives, solubilizers, dyes or, in particular, permeation promoters and complexing agents (eg cyclodextrins) can be used.
  • active substance carriers for example antioxidants, dispersants, emulsifiers, defoamers, taste correctors, preservatives, solubilizers, dyes or, in particular, permeation promoters and complexing agents (eg cyclodextrins) can be used.
  • the active substances can be administered rectally, by inhalation, parenterally (perlingually, intravenously, percutaneously) or orally.
  • the activity of cells can be reduced via the mitochondrial succinate dehydrogenase by reducing the tetrazolium Determine salt to formazan blue (Mosmann, Br. J. Cancer, 52: 205-214, 1983). The metabolic activity can then be used to infer the respective number of cells.
  • Cells were plated out in 80 ⁇ l medium using an automatic pipette (Elektrapette, Tecnomara).
  • the modulators to be examined were dissolved in 100% DMSO and then further diluted with medium. The final DMSO concentration was 0.1% in all batches. 10 ⁇ l cytostatics solution and 10 ⁇ l modulator solution were added to the cell culture. In the control, 20 ⁇ l of medium were pipetted accordingly.
  • the formazan formed was quantified using an automatic microtiter plate reader (EL 311, Bio-Tea Instruments) at 540 nm.
  • the reference wavelength was 690 nm.
  • the absorption data were given as mean values of a 3-fold determination + -SEM. Dose-response curves were obtained by plotting the formazan formation as a percentage of the control against the respective cytostatic concentration.
  • VCR 1000 was used as the cell line and VCR as the cytostatic agent.
  • concentration of the corresponding compounds was 0.5 ⁇ m in each case.
  • the numbers of the compounds examined correspond to the numbers in the examples.
  • the RMF value resistance modulation factor
  • the RMF value is the quotient of the IC50 value (ng / ml) cytostatic agent alone and the IC50 value cytostatic agent + investigated compound.
  • RMF value IC50 (ng / ml) cytostatic / IC50 (ng / ml) cytostatic + compound.
  • Multidrug resistant and sensitive cells of the t-lymphoblastoid leukemia cell lines CCRF VCR1000 and CCRF-CEM are removed from the cell culture and harvested by centrifugation.
  • Rhodamine 123 is then added (final concentration 0. 8 mg / 1) and incubated for a further h at 37 ° C.
  • the cellular rhodamine 123 fluorescence is measured with the aid of a fluorescence-activated line sorter.
  • the excitation wavelength is 488 nm.
  • the rhodamine 123 fluorescence is measured at 520 nm. Dose is obtained from the data obtained -Efficiency curves are created, the EC50 value of which is used as a measure of the potency of a modulator for abolishing the P-glycoprotein-mediated rhodamine 123 reduced accumulation.

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  • Organic Chemistry (AREA)
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Abstract

Des composés ayant la formule (I), dans laquelle les substituants et les symboles ont la notation donnée dans la description, sont des modulateurs intéressants de la résistance.
PCT/EP1993/003605 1992-12-23 1993-12-18 Derives anneles d'uracile WO1994014809A1 (fr)

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AU58133/94A AU5813394A (en) 1992-12-23 1993-12-18 Anellated uracil derivates

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CH3949/92-3 1992-12-23
CH394992 1992-12-23

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997019946A1 (fr) * 1995-11-24 1997-06-05 Byk Gulden Lomberg Chemische Fabrik Gmbh Pyridopyrimidines
WO1998017648A1 (fr) * 1996-10-18 1998-04-30 Xenova Limited Derives d'acide anthranilique utiles comme modulateurs de la resistance multiple aux anticancereux
WO2002102793A2 (fr) * 2001-06-19 2002-12-27 Warner-Lambert Company Llc Agents antibacteriens
US6693099B2 (en) 2000-10-17 2004-02-17 The Procter & Gamble Company Substituted piperazine compounds optionally containing a quinolyl moiety for treating multidrug resistance
US6864259B2 (en) 2001-05-30 2005-03-08 Warner-Lambert Company Antibacterial agents
US7094780B1 (en) 2000-01-24 2006-08-22 Warner Lambert Company Llc 3-aminoquinazolin-2,4-dione antibacterial agents
US7300908B2 (en) * 2001-07-05 2007-11-27 Basf Aktiengesellschaft Fungicidal triazolopyrimidines, method for the production thereof and use thereof in controlling noxious fungi and agents containing said compounds
CN100354265C (zh) * 1996-10-18 2007-12-12 埃克森诺瓦有限公司 邻氨基苯甲酸衍生物及其制备方法和作为多种抗性调节剂的用途

Citations (2)

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Publication number Priority date Publication date Assignee Title
WO1989007443A1 (fr) * 1988-02-19 1989-08-24 Byk Gulden Lomberg Chemische Fabrik Gmbh R-(-)-niguldipine optiquement pure et ses derives pour traiter des affections tumorales
EP0353692A2 (fr) * 1988-08-02 1990-02-07 Nissan Chemical Industries Ltd. Agent augmentant l'effet des produits antitumoraux

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1989007443A1 (fr) * 1988-02-19 1989-08-24 Byk Gulden Lomberg Chemische Fabrik Gmbh R-(-)-niguldipine optiquement pure et ses derives pour traiter des affections tumorales
EP0353692A2 (fr) * 1988-08-02 1990-02-07 Nissan Chemical Industries Ltd. Agent augmentant l'effet des produits antitumoraux

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5925642A (en) * 1995-11-24 1999-07-20 Byk Gulden Lomberg Chemische Fabrik Gmbh Pyridopyrimidines
WO1997019946A1 (fr) * 1995-11-24 1997-06-05 Byk Gulden Lomberg Chemische Fabrik Gmbh Pyridopyrimidines
WO1998017648A1 (fr) * 1996-10-18 1998-04-30 Xenova Limited Derives d'acide anthranilique utiles comme modulateurs de la resistance multiple aux anticancereux
GB2334521A (en) * 1996-10-18 1999-08-25 Xenova Ltd Anthranilic acid derivatives as multi drug resistance modulators
GB2334521B (en) * 1996-10-18 2000-10-04 Xenova Ltd Anthranilic acid derivatives as multi drug resistance modulators
US6218393B1 (en) 1996-10-18 2001-04-17 Xenova Limited Anthranilic acid derivatives as multi drug resistance modulators
CN100354265C (zh) * 1996-10-18 2007-12-12 埃克森诺瓦有限公司 邻氨基苯甲酸衍生物及其制备方法和作为多种抗性调节剂的用途
US7094780B1 (en) 2000-01-24 2006-08-22 Warner Lambert Company Llc 3-aminoquinazolin-2,4-dione antibacterial agents
US7582627B2 (en) 2000-01-24 2009-09-01 Warner-Lambert Company 3-aminoquinazolin-2,4-dione antibacterial agents
US6693099B2 (en) 2000-10-17 2004-02-17 The Procter & Gamble Company Substituted piperazine compounds optionally containing a quinolyl moiety for treating multidrug resistance
US6864259B2 (en) 2001-05-30 2005-03-08 Warner-Lambert Company Antibacterial agents
WO2002102793A3 (fr) * 2001-06-19 2003-04-10 Warner Lambert Co Agents antibacteriens
WO2002102793A2 (fr) * 2001-06-19 2002-12-27 Warner-Lambert Company Llc Agents antibacteriens
US7300908B2 (en) * 2001-07-05 2007-11-27 Basf Aktiengesellschaft Fungicidal triazolopyrimidines, method for the production thereof and use thereof in controlling noxious fungi and agents containing said compounds

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